Our overall hypothesis, based upon our preliminary data, is that in patients with insulin dependent diabetes mellitus (IDDM) iatrogenic hypoglycemia is a major cause of Hypoglycemia-Associated Autonomic Failure (HAAF), a disorder distinct from classical diabetic autonomic neuropathy and associated with an increased frequency of iatrogenic hypoglycemia), and that HAAf, by reducing both symptoms of and defenses against hypoglycemia, results in recurrent episodes of iatrogenic hypoglycemia thus creating a vicious cycle. To explore this in IDDM and controls we plan to: 1. Use the stepped hypoglycemic clamp technique to test the hypothesis that glycemic thresholds for neuroendocrine, including autonomic, responses to, and symptoms of, hypoglycemia change rapidly (hours) as a result of recent antecedent glycemia. 2. Use the insulin infusion test to test the hypothesis that changes in glycemic thresholds for neuroendocrine, including autonomic, responses to hypoglycemia caused by differences in recent antecedent glycemia result in corresponding changes in the ability to defend against hypoglycemia. 3). Use non- hypoglycemic stimuli (standing, cycle exercise, meal ingestion) to test the hypothesis that in contrast to classical diabetic autonomic neuropathy HAAF, caused by recent antecedent hypoglycemia, is specific for the stimulus of hypoglycemia. 4. Use peripherally acting (edrophonium) and centrally acting (physostigmine) cholinesterase inhibitors to test the hypothesis that HAAF is distinct from classical diabetic autonomic neuropathy, and the result of reduced central neural signaling rather than postganglionic neural failure (as in classical diabetic autonomic neuropathy). These data will provide the basis for study of our hypothesis that the mechanism of HAAF is increased fractional extraction of glucose from the circulation into tissues including the central nervous system. In addition to providing further insight into human glucoregulatory physiology and its pathophysiology in IDDM, these studies are expected to provide data relevant to the prevention of clinical hypoglycemia, a major unresolved problem that causes recurrent morbidity, and some mortality, in patients with IDDM.